• The CLASE Study: Endovascular Management of the Superficial Femoral Artery

      Shieh, Hester F.; The University of Arizona College of Medicine - Phoenix; Rodriguez, Julio (The University of Arizona., 2012-05-01)
      Objectives – The purpose of this study was to compare endovascular treatment modalities for peripheral vascular disease in the femoropopliteal arteries with respect to technical success, efficacy, and patency at mid-term follow up. Methods – A retrospective review of patients that underwent endovascular management of the femoropopliteal segment was conducted to evaluate patency. The CLASE study included five treatment arms: cryoplasty, laser, angioplasty/stent, Silverhawk atherectomy, and Viabahn endoluminal graft. Results – Between November 2004 and May 2009, 306 patients met inclusion criteria. There was a statistically significant difference in patencies among treatment groups (p=0.016), driven by laser having a significantly lower patency than the angioplasty/stent, Silverhawk atherectomy, and Viabahn endoluminal graft groups. Conclusions – Many of the expensive endovascular devices have poor patencies lasting less than six months. Angioplasty/stent is not inferior to these new devices, and may remain the standard of care.
    • Comparison of Common High-risk Pregnancy Conditions Between Health Start and Non-Health Start Participants

      Stump, Marla Krysteen; The University of Arizona College of Medicine - Phoenix; Lopez, Ana (The University of Arizona., 2012-05-01)
      Context: Health Start is a program run by the Arizona Department of Health Services (ADHS) that utilizes community health workers to educate at-risk pregnant women and new mothers throughout many of the underserved regions of Arizona. The Health Start Curriculum - the tool used to educate community health workers on prenatal and infant care - is currently undergoing a revision. This project is intended to examine medical risk factors and birth outcomes unique to Health Start participants in order to provide information that will be considered when revising the curriculum. Objective: To compare the prevalence of medical risk factors and selected birth outcomes of women actively enrolled in Health Start to their age-matched, race/ethnicity-matched, and delivery method-of-payment-matched counterparts. Methods: A cross-sectional study was conducted at the Arizona Department of Health Services Bureau of Women’s and Children’s Health using the birth certificate data from women who gave birth in Arizona in 2009. A relative risk for each medical risk factor and birth outcome parameter was tabulated using chi-square analysis, and the 5 statistical significance was determined utilizing a p-value of 0.05 as the cutoff for statistical significance. Results: Overall the study revealed a significantly lower rates of anemia in active Health Start participants compared to inactive Health Start enrollees (1.4% vs. 7.2%, p-value = 0.001). The low relative risk of pre-term delivery for Health Start participants compared to matched controls approached statistical significance (5.8% vs. 10.1%, p-value = 0.057), but the power of the test was limited due to small sample size. Other medical risk factors and birth outcomes did not reveal a statistically significant difference between active Health Start participants and matched controls or active Health Start Participants and inactive Health Start enrollees. Conclusions: Active enrollment in the Health Start program is associated with significantly lower rates of anemia and notably lower rates of pre-term delivery. A follow-up study with a larger sample size is indicated to increase the power of the study.
    • A Comparison of Depression Screening Tools in Parkinson’s Disease and Normal Community Controls Using a Brain and Body Donation Database

      Rosen, Amanda; The University of Arizona College of Medicine - Phoenix; Shill, Holly (The University of Arizona., 2012-05-01)
      The purpose of this study was to review and compare a variety of depression inventories in Parkinson’s disease (PD) and normal controls (NC) to look for patterns or trends to help with clinical management of these patients. The study population consisted of subjects enrolled in a brain and body donation program who were receiving annual neurological and neuropsychiatric assessments. Statistical models were applied to the data to compare trends between screening tools, medications, and demographics. The frequency of depression was greater in PD cases than NC across the inventories. The greatest frequency of positive screens came from the Neuropsychiatric Inventory (NPI). Because the NPI requires an informant to administer, and had the highest percent of positive screens in both PD and NC groups, this study suggests that a caregiver or partner may be a helpful addition in clinical practice during depression screening in elderly patients with and without PD.
    • The Cryptic Peptides, Prepro-Thyrotropin Releasing Hormone 186-199 and 194-199, Suppress Anterior Pituitary Prolactin Secretion in vivo and in vitro

      Shortridge, Emily; The University of Arizona College of Medicine - Phoenix; Handa, Robert (The University of Arizona., 2012-05-02)
      Prepro-thyrotropin releasing hormone (ppTRH)-176-199 is one of several peptide fragments cleaved during TRH synthesis and has been implicated as a regulator of neuroendocrine function. ppTRH 176-199 has been shown to acutely inhibit the stress-induced rise in ACTH, corticosterone (CORT), and prolactin (PRL) in the rat. The receptor for ppTRH 176-199 currently remains unknown. In this study we sought to characterize the active domain of ppTRH 176-199 and, using in vivo and in vitro approaches, determine its role in regulating anterior pituitary secretion of PRL. The 186-199, 194-199, and 186-191 amino acid fragments of ppTRH were administered I.P. to adult male Sprague-Dawley rats 15 min. prior to a 20 min restraint stress to determine the peptide’s active moiety in regulating prolactin secretion. Animals were euthanized and plasma was saved for assay of circulating PRL using enzyme immunoassay (EIA). ppTRH 186-199 significantly attenuated the stress-induced rise in prolactin in male rats in a dose-responsive fashion. This effect was mimicked by ppTRH 194-199 but not by ppTRH 186-191. At the highest dose (10 mg/kg BW), ppTRH 194-199 also reduced the stress-induced rise in plasma CORT. Additionally, in vitro studies were performed using the rat growth hormone (GH)/PRL –secreting MMQ cell line. MMQ cells were treated with ppTRH 186-199 and media was assayed for PRL levels. Cells were harvested and examined for changes in PRL mRNA. Within 30 minutes following treatment of estradiol-stimulated MMQ cells with ppTRH 186-199 there was a decrease in media levels of PRL compared to vehicle. Furthermore, in MMQ cells that were primed with 10nM estradiol for 48 hours there was an increase in media PRL levels, which was reduced following ppTRH 186-199 treatment. After 4 hrs of treatment, the inhibitory effect of ppTRH 186-199 on PRL secretion from MMQ cells was only seen on estradiol-stimulated cells. There were no effects of ppTRH 186-199 when examined after 24 hrs of treatment. There were no effects of ppTRH 186-199 or 194-199 of PRL mRNA levels. These data suggest that the carboxy terminal fragment of preproTRH 178-199 contains all the activity of this ppTRH cryptic peptide for regulation of PRL and corticosterone secretion. This suggests a potential moiety responsible for interaction with the peptide’s receptor. The inhibitory effect of ppTRH 186-199 and 194-199 on media PRL levels and not on mRNA synthesis implicates it as an effector of hormone secretion rather than protein synthesis. The short-lived duration of its effects supports a role as 6 an acute effector of the PRL system. The target receptor of the ppTRH 178-199 fragment remains uncertain. However the use of ppTRH 194-199 as a peptide bait may prove useful in identifying the receptor.
    • Current Status of Transcatheter Aortic Valve Implantation: A Systematic Review of Non-orthodox Deployment Strategies

      Pan, Hao; The University of Arizona College of Medicine - Phoenix; Caskey, Michael (The University of Arizona., 2012-05-01)
      points included feasibility, safety, efficacy, and durability. Results: The current literature regarding TAVI is limited to observational studies. Overall procedural success rates ranged from 90% to 100%. The incidence of major adverse events included: 30-day mortality (0%-18%), major adverse cardiovascular and cerebral events ranged from 2% to 35% and the rate of postoperative multiple organ failure was 2% to 8%. There was statistically significant hemodynamic improvement demonstrated by postoperative echocardiography measurements with no significant deterioration up to 6 months postprocedure. Survival at 6 months ranged from 59% to 93%. Only 5 one study with long-term of transapical TAVI follow-up could reliably evaluate long-term survival of 58% at 3 years. Significance: TAVI has proven to be feasible and potentially an effective intervention for non-surgical patients with symptomatic aortic stenosis. Although short-term efficacy based on echocardiography has been promising, there is a paucity of data concerning long-term outcomes. The evolution of TAVI will be dependent on the development of a valid tool for estimating the surgical risk to define indications for surgical aortic valve replacement versus transcatheter aortic valve implantation.
    • Current Usage of Helicopter Ambulances Services in the State of Arizona

      Williams, Andrew R.; The University of Arizona College of Medicine - Phoenix; Campos-Outcalt, Douglas (The University of Arizona., 2012-05-01)
      The overall goals of this research project were threefold: to characterize how the Helicopter Ambulance system in Arizona is used for trauma, comparison of Ground and Helicopter Ambulance usage, and recommendations to facilitate effective use of the Helicopter Ambulance system. Data for this project were obtained from the Arizona Department of Health Services Trauma Registry. Analysis included descriptive statistics, crosstabulation, calculation of two-year usage rates, and Z-score (for proportions) comparison between Ground and Helicopter Ambulance for statistical significance (using SPSS18/20). The American Indian/Alaska Native population was the most frequently transported (two-year rate 1572.3/100,000 population; all transport methods). Gila County and Yuma County had the highest rates of Ground Ambulance transport (Gila 1016.8/100,000, Yuma 1161.7/100,000) whereas Maricopa County was much lower (431/100,000). For Helicopter Ambulance use, the most common counties of transport were Navajo and Gila (414.1/100,000 and 606.4/100,000) whereas Maricopa county was much lower (24.2/100,000). 5 The significance of this project comes in the area of recommendations for system improvement. Recommendations include ground-based triage areas to determine whether a patient should be transported to a Level I trauma center (or whether a lower level of care is acceptable), as well as how the patient should be transported (Helicopter v. Ground Ambulance).
    • Defining 1H-MRS Criteria Used to Differentiate Brain Tumor from Radiation Necrosis

      Crain, Ian; The University of Arizona College of Medicine - Phoenix; Preul, Mark (The University of Arizona., 2012-04-30)
      An effective modality for differentiating recurrent brain tumor from post-treatment radiation effect remains elusive. The average survival time after diagnosis of high grade brain tumors is one year. It is imperative to maximize currently available interventions to increase survival. One potential imaging technique to differentiate tumor recurrence from treatment effect is 1H-MRS. It is currently unknown how this imaging modality performs this task in the clinical setting. This study presents a variety of cases that represent the spectrum of 1H-MRS use, interpretation, and outcomes of patients with gliomas at a high volume tertiary treatment facility. The state of 1H-MRS use for differentiating tumor recurrence from radiation necrosis demonstrates a need for better techniques and criteria for interpretation of acquired 1H-MRS information.
    • Design Requirements of Educational EHR for use in Case Based Instruction of First and Second Year Medical Students

      Germain, Michael; The University of Arizona College of Medicine - Phoenix; Silverman, Howard (The University of Arizona., 2012-04-30)
      Case based instruction (CBI) in medical education is a well established alternative to lecture format in the training of first and second year medical students. There have been previous documented attempts to include technology in CBI that have received positive feedback from students. Electronic health records are now being mandated by 2014 and historically there have been many barriers to adoption including lack of EHR technical skills by physicians. As a result, biomedical informatics education is being integrated into medical school curriculum with hope that better understanding of medical applications will prepare future physicians to utilize them. There has been no documented evidence of successful utilization of a commercial grade EHR within CBI despite many potential benefits in doing so. Previous attempts at accomplishing this task have been discovered but multiple challenges were encountered in developing a suitable educational EHR and as a result the attempt was unsuccessful. The following is a design project with the aim of highlighting specific design requirements, as well as, a theoretical usage scenario of a commercial grade EHR in CBI. Outlined as well is experimental design for future evaluation of such a system. There will be many 4 technological challenges that will need to be overcome and numerous resource requirements to get such a project functional. Despite this, all aspects of such a system are technologically feasible. Completion of such a system could result in potential commercial benefit and provide a platform for further investigation of early EHR training effect on physician-EHR acclimation.
    • Diffusion-based Heterogeneity Models in Magnetic Resonance Imaging for Characterization of Brain Tumors: An Introductory Study

      Goettl, Christopher; The University of Arizona College of Medicine - Phoenix; Karis, John (The University of Arizona., 2012-04-30)
      Recently developed diffusion-based magnetic resonance (MR) protocols have proven useful in assessing the heterogeneity of water diffusion in neural tissues, including brain tumors1. Based on theoretical increase in tumor cell heterogeneity compared to healthy brain2, these emerging imaging modalities offer several potentially useful applications, such as in identifying tumor margins, establishing tumor type and grade, and for differentiating tumor recurrence from post-treatment effect. In this study an introductory subset of five patients were scanned using a multi b-value Diffusion-Weighted Image (DWI) sequence, fitted with two previously described higher-order diffusion models. The first utilized a stretched exponential model (α-DWI)3; the second applied a cumulant expansion model (Diffusional Kurtosis Image, DKI)4. These models quantified water diffusion heterogeneity using the fitted parameters α and Kapp, respectively. The intent of this project was to gauge the potential utility of these MR models to apply diffusion heterogeneity information for characterization of brain tumors. Early results confirmed initial 6 hypotheses for high-grade gliomas, that (1) diffusion heterogeneity appeared greater in tumoral regions than in surrounding tissue, (2) high-grade tumors exhibited a relatively more heterogeneous diffusion pattern (lower α and higher K app) compared with low-grade glioma, and (3) the metastatic tumor had unique diffusion behavior compared to the primary tumors. Overall, this introductory study generally supports the potential ability of higher-order diffusion heterogeneity models to characterize brain tumors. More detailed investigation of this application across a larger subset of patients and tumor types may be beneficial.
    • Doctoring and Disabilities: Analyzing the Implementation of a Disabilities-focused Clinical Skills Program for Second-year Medical Students

      Churgin, Daniel; The University of Arizona College of Medicine - Phoenix; Campagnolo, Denise (The University of Arizona., 2012-04-30)
      Objectives: To investigate second-year medical students’ change in comfort level after a disabilities-focused interactive session, with regards to disability etiquette and greeting, interviewing, and examining patients with disabilities. Setting: The University of Arizona College of Medicine, Phoenix Campus, doctoring suites. Students interacted in a clinical setting with volunteers with disabilities, including volunteers with blindness, deafness, mobility impairment, and language impairment. Students received 3 surveys during the study duration: the first before the event, the second after they had prepared for the event with didactic materials, and the third after the event. Participants: 46 second-year medical students participated in the event, and 29 students completed all surveys. Methods: Survey data was analyzed using paired t-tests wherever possible, with P <0.05 being interpreted as significant. Results: Comfort level for disability etiquette and greeting, interviewing, and examining patients with disabilities improved significantly for patients with blindness, deafness, mobility impairment, and language impairment. Although this change was significant for most measures from pre-event to post-event, it was significant for every measure from post-materials to post-event. Conclusion: A pre-clinical disabilities event in which second-year medical students interact with people with disabilities is effective in increasing student comfort level.
    • Establishing the Demographics and Rationale for Use of Preimplantation Genetic Diagnosis and Screening in Arizona and Outlying Locations

      Sprunger, Victoria; The University of Arizona College of Medicine - Phoenix; Hunt, Katherine (The University of Arizona., 2012-05-01)
      Background: Pre-implantation genetic diagnosis (PGD) and pre-implantation genetic screening (PGS) test for genetic diseases prior to implantation in cases utilizing in-vitro fertilization. While PGD/PGS use is expanding, ramifications for patients and society are unclear. Study Question: What is the current utilization and patient demographics of Preimplantation Genetic Diagnosis (PGD) and Preimplantation Genetic Screening (PGS) in Arizona Infertility clinics? Significance: Though PGD/PGS usage has grown, gaps remain in the understanding of current U.S. clinic experience. This study addresses these, focusing on the diverse Arizona patient population, by surveying all Arizona in-vitro fertilization clinics. Methods: Using capture-recapture method, all IVF-providing clinics within Arizona (n=11) were identified and sent an anonymous survey. Surveys were then analyzed. Results: Nine of eleven clinics responded. While patient demographics were similar, patient numbers per clinic differed and were not correlated with length of operation. Genetic tests differed amongst 5 clinics. Most favored self-regulatory models, recognized the Internet as the primary source of patient education, and valued increased PGD/PGS education. Conclusion: Patient demographics revealed that minority populations were not proportionally represented when compared to census data. Clinics offered differing sets of genetic tests and criteria for seeking these tests, indicating varying opinions amongst clinics about the ethicality of PGD/PGS.
    • Focusing on the Patient Encounter to Improve Adult Immunization Rates

      Moore, David A.; The University of Arizona College of Medicine - Phoenix; Birkholz, Karla (The University of Arizona., 2012-05-01)
      Objective: Healthy People 2010 established target goals for the percentage of adults immunized against Pneumococcus and seasonal influenza. Our objective was to create a vaccine program to allow our family practice clinic to reach these goals. Methods: Initial chart review (n=50) determined our clinic’s baseline percentages for Pneumococcus and billing records identified the number of influenza vaccines administered the previous year. We developed a vaccine program focused on direct intervention and executed it in two six-month phases; the first focused on seasonal influenza, and the second targeted Pneumococcus. We determined program efficacy of phase one (influenza) via shot volume and phase two by measuring post-program vaccine percentages thru a second chart review (n=104). Results: Pneumococcal coverage for adults age ≥65 dropped from 47 to 39% [95% CI: 23-71% & 22-56%], well short of the Healthy 4 People 2010 target of 90%. We measured a 16% volume increase in the administration of the seasonal influenza vaccine. Significance: Vaccines have tangible and positive effects on patient health. Direct intervention is an effective method for physicians to improve vaccine percentages, but is costly and time consuming.
    • GWAS for Bipolar Disorder in a European Cohort with CNV Discovery

      Mitropanopoulos, Sotiris; The University of Arizona College of Medicine - Phoenix; Craig, David (The University of Arizona., 2012-04-30)
      Background: Bipolar disorder (BD) is a disabling disorder whereby individuals suffer from episodes of mania and depression. The mode of inheritance of BD is complex and likely multifactorial. The specific number of susceptibility loci, the recurrence risk ratio attributable to each locus, and the degree of interaction between loci are unknown. By determining whether single nucleotide polymorphisms (SNPs) or copy number variants (CNVs) predispose individuals to bipolar disorder, therapeutics and diagnostic tests may be developed. Method: A Genome Wide Association Study (GWAS) was performed using cases of bipolar disorder and normal controls hybridized on Affymetrix 6.0 Genome-Wide Human SNP Arrays. Data preprocessing removed 595 individuals from 2205 arrays. The probe intensities of the remaining 880 cases and 730 controls were normalized. A modified t-test algorithm was used to determine p-values for each SNP. A sliding window analysis was performed on SNPs ordered by chromosome and locus. The mean probe intensities of the cases and controls from regions of significance were then reanalyzed for differences. Results: Analysis yielded several SNPs and CNVs that may have involvement in the pathophysiology of bipolar disorder. One region was 15kbp within the Neuron Navigator 2 (NAV2) gene. A second region was found in the Down Syndrome Cell Adhesion Molecule Like 1 (DSCAML1) gene. A third region was within the Voltage-dependent Calcium Channel Alpha 1G (CACNA1G). Conclusion: Multiple SNPs and CNVs may play a role in the phenotype of Bipolar Disorder. A convergent functional genomics approach with a gene network analysis maybe warranted elucidating possible pathophysiologies involving the gene products found to be significant in this study.
    • Imaging Evaluation of the Solitary Pulmonary Nodule

      Van Tassel, Lora; The University of Arizona College of Medicine - Phoenix; Korn, Ronald (The University of Arizona., 2012-05-01)
      An estimated 150,000 solitary pulmonary nodules (SPNs) are identified at chest radiography each year, making it important for physicians to understand how to characterize them and evaluate patients for potential malignancy. We performed an extensive literature search to identify risk factors, characteristics of SPNs, and available technologies used to identify and evaluate these nodules through a comprehensive literature search. Additionally, we present evidence-based management schemes for incidentally identified nodules. CONCLUSIONS: A number of features visible at thoracic CT are useful for determining whether an SPN is benign or malignant. FDG PET/CT plays an important role in the diagnosis and management of lung cancer and is an increasingly valuable tool for the characterization and management of SPNs. Unlike CT and MRI imaging, PET provides metabolic activity of a nodule. The information provided by PET/CT imaging allows for both morphological and anatomical characteristics as well as physiological data in the form of metabolism within the nodule itself. The information gained from PET is extremely useful for directing patient management and may obviate the need for invasive diagnostic procedures.
    • Incidence Estimates and Demographics of Scaphoid Fracture in the United States Population

      Van Tassel, Dane Carlisle; The University of Arizona College of Medicine - Phoenix; Wolf, Jennifer (The University of Arizona., 2012-05-01)
      Purpose: The epidemiology of scaphoid fracture occurrence is based mostly on retrospective analyses of small population centers. Analysis of a large injury database was performed with the hypothesis that previous studies have underestimated the incidence of scaphoid fracture. Methods: The National Electronic Injury Surveillance System (NEISS) is a probability sample of injuries in the United States presenting to emergency rooms. The NEISS model was queried for injuries classified as wrist fractures, and narrative data evaluated specifically for scaphoid fracture, over the 5-year period 2002-2006. Descriptive characteristics were analyzed with respect to patient demographics, location, mechanism, and sports/recreation participation. Results: A total of 507 injuries coded as fractures of the scaphoid comprised the dataset from 2002-2006, with weighted sampling estimating 21,481 scaphoid fractures nationwide during this time period. This results in an incidence rate for the US population of 1.47 fractures per 100,000 person-years (95% confidence intervals (CI), 1.31 to 1.63). 4 Conclusions: The NEISS dataset utilized in this study represents the largest single sample population for scaphoid fracture epidemiology in the medical literature. The estimated incidence of scaphoid fracture is higher in the U.S. than those reported for other countries.
    • The Incidence of Dysesthesia When Droperidol is Used for Prophylaxis of Post Operative Nausea and Vomiting

      Kassel, Kareem; The University of Arizona College of Medicine - Phoenix; Murray, Michael (The University of Arizona., 2012-04-30)
      Background: Multiple therapeutic regimens are used in an effort to attenuate the incidence of postoperative nausea and vomiting (PONV). Some drugs (e.g. dexamethasone, droperidol and scopolamine) are given preoperatively for prophylaxis in patients who are at increased risk of developing PONV. The use of droperidol has been associated with a relatively high incidence of dysesthesias (30% to 70%) in the outpatient setting, but we have not observed dysesthesias in most patients who receive it perioperatively. HYPOTHESIS: The incidence of dysesthesias in the perioperative period is less than that reported in the outpatient environment. Purpose: The primary goal was to determine the incidence of dysesthesia in patients treated with droperidol perioperatively for PONV. Secondary goals were to determine efficacy of droperidol for preventing PONV and the effect of droperidol on anxiety Methods: 30 patients who were at moderate to severe risk of developing PONV and met no exclusion criteria were asked to participate in the study. The consented patients completed a survey just prior to the intravenous administration of 0.625 mg of droperidol. 6 The survey was repeated 1 hour after the patient was admitted to the PACU Results: None of the patients reported dysesthesia (0%, p<.001). Patients also reported an average 2.2 point reduction on their 1-10 anxiety level after surgery and no patients complained of PONV. Conclusion: Dysesthesia from droperidol is much less common in the perioperative setting than has been reported in the outpatient setting. Based on result, low dose droperidol is expected to prove less likely to cause dysesthesias when used in the intraoperative setting for prophylaxis of PONV than reported in emergency departments and oncology clinics.
    • Investigating Molecular Mechanisms Driving Breast Cancer Metastasis into the CNS

      Holz, David R.; The University of Arizona College of Medicine - Phoenix; Tran, Nhan (The University of Arizona., 2012-04-30)
      This research project aims to identify unique candidate genes involved in breast cancer metastatic invasion into the central nervous system (CNS). The goal of this study focuses on studying and comparing the genomes of two distinct breast cancer cell lines that model a primary breast cancer and a CNS metastatic variant. These cell lines were established by Yoneda et al. by employing six serial rounds of tumor injection into mice followed by CNS isolation to select a unique clonal cell line that consistently metastasizes to the CNS. Denoted MDA MB-23-BR and MDA MB-231-P by their predilection for CNS metastasis and primary breast tumor growth patterns, respectively, this cell line pair represents a unique functional model for comparing a primary breast cancer and a CNS metastatic clone. Hypothesis: We hypothesized that the BR clone's predilection for CNS metastasis is likely due to unique genetic alterations either at a chromosomal or gene expression level that differ from the primary breast tumor line. The goals of this study aimed to probe the genomes of the MDA MB-23-BR and MDA MB-231-P using array CGH and microarray gene expression profiling to identify these potential 5 differential chromosomal patterns and distinct gene expression profiles between the Br and P cell lines. Results: Initial studies to assess the invasive properties of the BR and P lines showed an approximate five-fold increase in invasion of the BR line compared to the P line by employment of a modified Boyden chamber invasion assay. Results of the array CGH analysis did reveal small regions of relative chromosome loss of the BR line on chromosome 1 and chromosome 10. Results of the gene expression array analysis revealed 138 genes with either 2-fold overexpression or underexpression between the BR and P lines. Canonical Pathway analysis revealed two genes, ADAM19 and GAB1, that may play a role in cell survival and metastasis. Significance: This study successfully identified unique chromosomal and gene expression differences between the MDA MB-231 P and, BR cell lines. These differences, though preliminary, may represent unique genetic regions and genes that facilitate breast cancer metastasis to the CNS and could serve as novel candidates for both biomarker development and chemotherapeutic intervention.
    • Investigating the Role of IGF-1 Receptor in Glioma Cell Survival, Migration and Proliferation

      Sen, Lilia F; The University of Arizona College of Medicine - Phoenix; Berens, Michael (The University of Arizona., 2012-05-01)
      Glioblastoma (GB) is the most common primary brain tumor, distinctive by its aggressive, highly invasive, angiogenic and necrotic presentation. The Insulin-like growth factor (IGF) pathway plays an important role in cancer cell proliferation, survival and migration. This study was initiated to investigate the role of the IGF-1 receptor in glioma cell survival, migration and proliferation. We tested glioma cells’ response to IGF1 receptor inhibition and whether the response is dependent on the endogenous levels of pIGF1R β (phosphorylated IGF receptor). We used a small molecule inhibitor of IGF1R, Tyrphostin AG1024, to test for dose-dependent apoptosis and for sensitization to the combination treatment with temozolomide, an oral alkylating agent used for the treatment of Grade IV astrocytoma. We also observed that glioma cell migration and proliferation may depend on the endogenous level of pIGF1R β. Because IGF1R is widely expressed in healthy and malignant cells, development of therapeutic uses for IGF1R-inhibitors will require defining additional genomic or proteomic characteristics. This would confer differential vulnerability between tumor and normal cells. Further investigation is needed to determine the molecular predictors of a glioma cell’s response to IGF1R inhibition.
    • Investigation of Cytarabine Resistance: Targeting the Cell Cycle Checkpoints and Strategies for Overcoming Resistance of Acute Myeloid Leukemia to Cytarabine

      Buechel, Megan; The University of Arizona College of Medicine - Phoenix; Tibes, Raoul (The University of Arizona., 2012-04-30)
      Patients diagnosed with Acute myeloid leukemia (AML) often become resistant to standard chemotherapeutic regimens. Cytarabine, a nucleoside analog, is the standard of care therapy for AML treatment. We hypothesized that by using an siRNA platform to inhibit 572 kinases in combination with Ara-C (cytarabine) in two AML cell lines (THP-1 and TF-1) we would be able to identify potential therapeutic targets to improve sensitivity to Ara-C (cytarabine). Our siRNA screen identified CHK1 as the most potent sensitizer to Ara-C. However, other kinases involved in DNA repair and checkpoint activation also improved sensitivity of cells to Ara-C. Checkpoints are present at the G1/S transition, within S phase and at the G2/M transition. Within the G2/M checkpoint, CHK1 functions to halt the transition to mitosis when DNA damage is detected. Additional siRNA screening of proteins that function in the G2/M checkpoint identified WEE1 as a potent sensitizer as well. It is hypothesized that abrogation of the G2/M checkpoint prevents repair pathways from repairing genotoxic damage caused by chemotherapeutics. Therefore, a literature review of the checkpoint targeting and rational therapeutic targets for future treatments was conducted. Both WEE1 and CHK1 are currently 4 being targeted in order to enhance activity of various genotoxic chemotherapeutics in many different cancers and present rational targets for further investigated in combination with Ara-C in AML.
    • Modulation of Alzheimer’s Disease related APP Trafficking via Protein Kinase C

      Vithana, Rukmalee; The University of Arizona College of Medicine - Phoenix; Valla, Jon (The University of Arizona., 2012-05-01)
      Chronic phorbol ester treatment treatment of a neuroblastoma cell line, SH-SY5Y, was hypothesized to induce alterations in APP expression and trafficking such that the holoprotein will increasingly localize to mitochondria. Fluorescent immunocytochemistry and confocal microscopy was used primarily to visualize co-localization of Amyloid precursor protein (APP) to Translocase complex of the outer mitochondrial membrane (TOMM machinery) on the mitochondria. Co-localization experiments were inconclusive in showing that chronic phorbol 12-myristate 13- acetate (PMA) treatment affects APP trafficking to mitochondria. Due to those results, mitochondrial gradient fractionation experiments and subsequent western blots were started to determine if there was increased APP expression at the mitochondrial membrane and if protein kinase C (PKC) was activated by chronic PMA treatment.